11, 12-dihydroxy steroids of the pregnane series and acetals and ketals thereof



United States Patent 3,240,778 11,12-DIHYDROXY STEROIDS OF THE PREGNANESERIES AND ACETALS AND KETALS THEREOF Patrick A. Diassi, Westfield,N.J., assignor, by mesne assignments, to E. R. Squibb & Sons, Inc., NewYork, N.Y., a corporation of Delaware N0 Drawing. Filed July 13, 1964,Ser. No. 382,344 18 Claims. (Cl. 260-23955) and wherein the 1,2-positionis saturated or double-bonded, the curvy lines indicate that the oxygencontaining radical is in either the alpha or beta position, R is hydroxyor u-acyloxy (preferably the acyloxy radical of a hydrocarbon carboxylicacid of less than twelve carbon atoms) P is hydrogen, lower alkyl, halolower alkyl, carboxy lower alkyl (or a salt or ester thereof),monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl,monocyclic heterocyclic or monocyclic heterocyclic lower alkyl, and Q islower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or esterthereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl loweralkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl,or together with the carbon atom to which they are joined P and Q arecycloalkyl or monocyclic heterocyclic. Particularly preferred are thosecompounds wherein P is lower alkyl and Q is lower alkyl or monocyclicaryl.

The final compounds of this invention are physiologically activesteroids which possess progestational activity and thus can be employedinstead of progestational agents, such as progesterone, for example, inthe treatment of habitual abortion, for which purpose they can beadministered in the same manner as progesterone, for example, with thedosage adjusted for the relative potency of the particular steroid.

The novel products of this invention are prepared by the processes ofthis invention which entail a number of steps starting with a3,20-bis-ketal of 9a-fluoro-l1-ketoprogesterone, such as the3,20-bis-ethylene ketal. The steps of the process may be represented bythe following equations, wherein R, P and Q are as hereinbefore defined,and A is preferably a lower alkylene radical, such as ethylene,propylene-1,2, and trimethylene:

CH3 CH3 I l O A O 0:

In accordance to the first step in the process of this invention a3,20-diketal of 9a-fluoro-ll-ketoprogesterone (Compounds A), such as the3,20-bis-ethylene ketal, is reacted with methyl lithium in the presenceof excess methyl iodide to yield the corresponding 3,20-diketal of1la-hydroxy-12-ketoprogesterone (Compounds B),

Compounds B are then either reacted with a strong base, such as analkali metal hydroxide (e.g., potassium hydroxide) to yield thecorresponding 3,20-diketal of 11- keto-lZfi-hydroxy-progesterone(Compounds D) or with lithium aluminum hydride to yield thecorresponding 3,20- diketal of 1la,-l2a-dihydroxyprogesterone (CompoundsC).

Compounds C are then reacted with a ketone or an aldehyde of at leasttwo carbon atoms, the reaction preferably being carried out by treatinga suspension or solution of the steroid in the ketone or aldehyde (or anorganic solvent if the ketone or aldehyde is a solid) with an acidcatalyst (e.g., perchloric acid, p-toluene sulfonic acid, andhydrochloric acid), neutralizing the acid and recovering the11cc,12oc-CyCliC ketal or acetal of 11a,12oc-dihydroxyprogesterone(Compounds E) formed.

Compounds E may then be hydrolyzed to yield Cornpound H, which can thenbe reacetalized or reketalized by treatment with an aldehyde or ketoneto yield Compounds E having different P and/or Q groups. Compounds H canalso be formed by hydrolyzing Compounds C by treatment with a mineralacid.

Among the suitable ketones and aldehydes that can be used in this stepof the processes of this invention may be mentioned the lower alkanalsof at least two carbon atoms, such as paraldehyde, propanal, andhexanal; di(lower alkyl)ketones, such as acetone, diethylketone,dibutylketone, methylethylketone, and methylisobutylketone;cycloalkanones, such as cyclobutanone, cyclopentanone, cyclohexanone,suberone, and cyclodexanone; mono and dicycloalkyl ketones, such ascyclohexylmethylketone and dicyclopropylketone, halo-lower alkanals,such as chloral hydrate, trifluoroacetaldehyde hemiacetal, andheptafiuorobutanal ethyl hemiacetal; halo-lower alkanones, such as1,1,1-trifiuoroacetone; monocyclic carbocyclic aromatic aldehydes, suchas benzaldehyde, halobenzaldehydes (e.g., p-chlorobenzaldehyde andpfluorobenzaldehyde), lower alkoxybenzaldehydes (e.g., o-anisaldehyde),di(lower alkoxy)benzaldehydes (e.g., veratraldehyde),hydroxybenzaldehydes (e.g., salicylaldehyde), dihydroxybenzaldehydes(e.g., resorcyaldehyde), lower alkyl benzaldehydes (e.g., m-tolualdehydeand pethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g., o,p-dimethyl-benzaldehyde), nitrobenzaldehydes, acylamidobenzaldehydes(e.g. N-acetylanthranilaldehyde), and cyanobenzaldehydes; monocycliccarbocyclic aromatic lower alkanals, such as phenylacetaldehyde, OL-phenylpropionaldehyde, 18-phenyl-propionaldehyde, 'yphenylbutyraldehyde,and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl,nitro, acylamido and cyano derivatives thereof; monocyclic heterocyclicaldehydes, such as picolinaldehydes, furfural, thiophene carbonals, andhalo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivativesthereof; monocyclic heterocyclic lower alkanals; l-(monocycliccarbocyclic aromatic) substituted lower alkanals, such as acetophenone,a,a,m trifiuoroacetophenone, propiophenone, butyrophenone,valerophenone, isocaprophenone, halo-phenyl lower alkyl ketones (e.g.,p-chloroacetophenone and pchloropropiophenone), (lower alkoxy)phenyllower alkyl ketones (e.g., p-anisyl methyl ketone), di(lower nitrophenyllower alkyl ketones alkoxy) phenyl lower alkyl ketones, hydroxyphenyllower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g.,resacetophenone), (lower alkyl)phenyl lower alkyl ketones (e.g., methylp-tolyl ketone), di(lower alkyl) phenyl lower alkyl ketones (o,p-xylylmethyl ketone),

(e.g., p-nitroacetophenone), acyl-amidophenyl lower alkyl ketones (e.g.,acetyl anilines), and cyanophenyl lower alkyl ketones; benzophenone, andmono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro,acylamido and cyano derivatives thereof; monocyclic carbocyclic aromaticlower alkanones, such as 1-phenyl-3-butanone and lphenyl-4-pentanone,and aromatically substituted derivatives thereof; l-(monocyclicheterocyclic)- substituted lower alkanals, such as 2-acetylfuran,Z-benzoylfuran, and Z-acetylthiophene; oxo substituted monocyclicheterocyclics, such as alloxan; monocyclic heterocyclic lower alkanones,and oxo lower alkanoic acids such as glyoxylic, pyruvic, acetoacetic,,G-ketopropionic, a-ketobutyric, levulinic, fi-keto-caproic andB-ketocaprylic acid [as well as salts and esters thereof, such as thelower alkyl esters (e.g., methyl and ethyl)].

If a keto acid is employed as the acetalizing or ketalizing agent,although the free acid may be used as such, thereby directly yieldingthe free acid derivative, a preferred method for forming thesederivatives is by an initial reaction with an ester of the desiredketoacid and subsequent hydrolysis of the ester derivative, as bytreatment with a dilute mineral acid, to yield the free acid derivative.The free acid can then, if desired, by neutralized With any desired base(preferably ammonium hydroxide or an alkali metal hydroxide, such assodium hydroxide and potassium hydroxide), to yield the salt derivative,or esterified by reaction with the desired alcohol (preferably a loweralkanol, such as methanol),

listed, to yield the corresponding 11p,12,8-cyclic ketals and acetals of11B,12/8-dihydroxyprogesterone (Compounds G).

Compounds D can also be reacted with an alkali metal, such as sodiummetal, to yield the corresponding 3.20- bis ketal of11a,IZfl-dihydroxyprogesterone (Compound I) which can then behydrolyzed, as by treatment with a mineral acid, such as sulfuric acid,to yield the free 11a,1Zfl-dihydroxyprogesterone (Compound J). Reactionof Compound I with a ketone or an aldehyde of at least two carbon atoms,such as one of the aldehydes or ketones previously mentioned, under thesame conditions previously listed, yields the corresponding11a,12;3-cyclic ketals and acetals of 1la,12,8-di'hydroxyprogesterone(Compounds K). Compounds K can also be prepared di ectly from CompoundsI under the same conditions, the acid present serving to hydrolyze the3,20-bis ketal groups.

Compounds G can be hydrolyzed to yield the free1118,12fi-dihydroxyprogesterone (Compound L). This compound can also beprepared by hydrolyzing Compounds F by treatment With a mineral acid,such as sulfuric acid.

11,9,12a-dihydroxyprogesterone can be prepared by treating11B,l2fi-oxidoprogesterone with perchloric acid. This compound, as wellas all other compounds disclosed that contain a free 12a-hydroxy group,can then be esterified in the usual manner, by treatment with the acylchloride or acid anhydride of the desired acid. The preferred acids arethose of hydrocarbon carboxylic acids of less than twelve carbon atoms,as exemplified by the lower alkanoic acids, the aromatic carboxylicacids (e.g., benzoic acid), the aralkanoic acids (e.g., phenacetic andfl-phenylpropionic acid), the cycloalkane carboxylic acid and thecycloalkene carboxylic acids.

If a l-dehydroprogesterone derivative is desired, the resulting11,12-oxygenated steroid (Compounds E, F, G, H, J, K,11B,1Za-dihydroxyprogesterone and esters of those compounds containing a12ahydroxy group) are treated. with2,3-dichloro-5,6-dicyanobenzoquinone, preferably at an elevatedtemperature, such as the reflux temperature of the solvent used todissolve the steroid, to yield the corresponding l-dehydro derivativesof the starting steroids.

In addition to Compounds E, G, H, l, K, L, llfi,120cdihydroxy-progesterone and esters of those compounds containing a12a-hydroxy group, Compounds B, C and F are new intermediates of thisinvention.

The following examples illustrate the invention (all temperatures beingin centigrade):

Example 1 .-A -pregnene-11u-0l-3,12,20-tri0ne 3,20-bis-ethylene ketal To453 g. of lithium shot previously washed with three, two-liter portionsof ether, 28 l. of anhydrous ether are added followed by 3.26 l. ofmethyl iodide which are added slowly at such a rate as to maintain acontrolled reflux.

A solution of 1.405 kg. of 9a-fluoro-A -pregnene-3J1, ZO-trione3,20-bisethylene ketal in 14 l. of dry benzene is then added slowly withstirring so as to maintain the temperature at 26-36. The reactionmixture is kept at 24 for 15 hours after which the excess reagent isdestroyed by the careful addition of 4.1 of methanol, followed by 18 l.of water. The organic phase is separated, and the aqueous phase isextracted three times with 15 1. portions of benzene. The combinedorganic phases are then Washed with water to pH 6.8, dried over sodiumsulfate and concentrated, in vacuo. The crystals which separate arefiltered, Washed with warm hexane and dried to give about 674 g. of A-pregnene-11a-ol-3,12,20-trione 3,20-bisethylene ketal having a meltingpoint of about 224-226", [a] +2.90 (chf.).

I 6 Example 2.A -pregnene-12;6-0l-3,11,20-tri0ne 3,20-bis-ethylene ketalTo a solution of 50 g. of potassium hydroxide in a mixture of 875 m1. ofmethanol and 125 ml. of water, 5 g. of A pregnene-11a-ol-3,12,20-trione3,20- bisethylene ketal are added and the mixture refluxed for 3 hours,

. during which time the steroid dissolves and the solution turns amber.The solution is then cooled, diluted with 2 liters of water andextracted with ethyl acetate. The ethyl acetate extracts are combined,washed with Water until neutral, dried over sodium sulfate andevaporated to dryness, in vacuo. Crystallization of the residue fromacetone gives about 3.56 g. of A -pregnene-12fl-ol-3J1,20- trione3,20-bisethylene ketal having a melting point of about 186-188.

Example 3 .A -pregnene.-1 1 13,1 2/8-diol-3 ,ZO-dione 3,20-bisethyleneketal To a solution of 101.6 mg. of. A -pregnene-12/8-ol-3,l1, ZO-trione3,20-bisethylene ketal in 25 ml. of tetrahydrofuran, freshly distilledfrom lithium aluminum hydride, 103.6 mg. of lithium aluminum hydride isadded in small portions over a five-minute period. The mixture is thenrefluxed for three and one-half hours, cooled and the excess reagentdecomposed by the careful addition of ethyl acetate. The mixture is thendiluted With water, extracted with chloroform, the chloroform extractscombined, washed with water and evaporated to dryness, in vacuo.Crystallization of the residue from acetone-hexane gives about 72.3 mg.of A pregnene-11 8,12,B-diol-3,20-dione 3, ZO-bisethylene ketal having amelting point of about 208- 210", [a] 35.3 (chf.).

AnaIysis.-Calcd. for C H O (434.55): C, 69.09; H, 8.81. Found: C, 69.04;H, 8.84.

Example 4 .A -pregnene-1 1 (1,1 2a-di0l-3,20-di0ne 3,20-bl'sethyleneketal To a solution of 1.0 g. of A -pregnene-11a-ol-3,12,20- trione3,20-bisethylene ketal in 75 ml. of tetrahydrofuran, freshly distilledfrom lithium aluminum hydride, 1 .0 g. of lithium aluminum hydride isadded in small portions over a five-minute period. Then, following theprocedure of Example 3, there is obtained about 900 mg. of A-pregnene-l1u,l2a-diol-3,20-dione 3,20-bisethyleneketal having a meltingpoint of about ZZZ-224, [a] -26.1 (chf.).

Analysis.-Calcd. for C H O (434.55): C, 69.09; H, 8.81. Found: C,69.03;H, 8.86.

Similarly, if 9a-fluor-o-A -pregnene-3J1,20-trione 3,20--bis-l,2-propylene ketal and 9a-fluoro-A -pregnene-3J1,20- trione3,20-bis-trimethy'lene ketal are substituted for the bisethylene ketalin the procedure. of Example 1 and the procedures of Examples 2, 3 and 4are followed, the corresponding 3,20-bis-l,2-propylene ketal and3,20-bistrimethylene ketal derivatives are obtained, respectively.

Example 5 .1 1 3,1 2 B-dihydroxy progesterone 1 1 ,1 Z-acetonz'de A313238 m (e=17,000)

Analysis.Calcd. for C H O (386.51): C, 74.57; H, 8.87. Found: C, 74.64;H, 8.77.

7 Example 6.] I 5,] 2 fl-dilz ydroxy progesterone 11,12-acetpl1enonideFollowing the procedure of Example but substituting freshly distilledacetophenone for the acetone there is obtained11B,12B-dihydroxyprogesterone 11,12-acetophenonide.

Similarly, if any of the other aldehydes or ketones specifically listedhereinbefore is substituted for the acetone in the procedure of Example5, the corresponding 11,12- cylic acetal or ketal derivative of1113,12B-dihydroxyprogesterone is obtained.

Example 7.-] 1 a,I2a-dihydr0xypr0gesterone 11,12-acetonide Example 8 .-11 a,I2a-dihydroxyprogeslerone 11,12-acet0phen0nide A solution of 303 mg.of A -pregnene-11a,12a-diol-3, 20-dione, 3,20-bisethylene ketal in 15ml. of freshly distilled acetophenone containing 0.075 ml. of perchloricacid is left at room temperature for 68 hours. The reaction is thenneutralized with 5% sodium bicarbonate, diluted with water and extractedwith chloroform. The chloroform extracts are washed with water andevaporated to dryness, in vacuo. Chromatography of the residue on Woelmneutral alumina (Activity V) gives 11a,12u-dihydroxyprogesterone11,12-acetophenonide.

Example 9.1 1 a,] Za-dihyd roxy-I -dehydr0 progesterone11,12-acet0phen0nide A solution of 224 mg. of11a,12a-dihydroxyprogesterone 11,12-acetophenonide and 125 mg. of2,3-dichloro- 5,6-dicyanoquinone in ml. of purified dioxane is refluxedunder nitrogen for 6 hours. The mixture is then filtered and theprecipitate washed with dioxane. The combined filtrate and washing isthen diluted with an equal volume of chloroform and adsorbed onto 10 g.of Woelm neutral alumina (Activity I). Elution with chloroform andevaporation of the solvent, in vacuo, gives a residue which oncrystallization from acetonehexane yieldsl1a,12a-dihydroxy-l-dehydroprogesterone 11,12-acetophenonide.

Example 10.-11,8,1ZB-dilzydroxy-I-dellydr0pr0gesterone 1 1,lZ-acetophenonide Following the procedure of Example 9 but substituting11,8,1Z/S-dihydroxyprogesterone 11,12-acetophenonide for the11a,12a-dihydroxyprogesterone 11,12-acetophenonide, 116,12B-dihydroxy 1dehydroprogesterone 11,12-acet0- phenonide is obtained.

Example 11 11 3,12u-dihydroxyprogesterone To a solution of 200 mg. of115,12fl-oxidoprogesterone in 3.5 ml. of dioxane 1.7 ml. of 2 molarperchloric acid are added and the solution left at room temperature fortwenty four hours. The solution is then diluted with 25 ml. of water andextracted three times with chloroform. The combined chloroform extractsare washed with water and evaporated to dryness, in vacuo. The residueon crystallization from acetone-hexane gives about 158 mg. of 113,1Za-dihydroxyprogesterone having a melting point of about 180181, [04+186 (chloroform),

Analysis.-Calcd. for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.76;H, 8.73.

Example 12.] 1B,IZa-dilzydroxyprogesterone 12-acetate A solution of 25mg. of 1lfl,12a-dihydroxyprogesterone in 3 ml. of dry pyridine and 1 ml.of acetic anhydride is kept at room temperature for sixteen hours. Thesolution is then diluted with ice water and extracted with chloroform.The chloroform extracts are washed with water, 2 N hydrochloric acid,and water again until neutral and evaporated to dryness, in vacuo. Theresidue is plate chromatographed using alumina (V) as adsorbent andchloroform as the developing solvent. The band having an R of 0.4 ondetection by U.V. is eluted with ethyl acetate and on crystallization ofthe residue after evaporation of the solvent from acetone-hexane givesabout 11.3 mg. of 11,8,l2u-dihydroxyprogesterone l2-acetate having amelting point of about 238240, [Q +203 (chloroform),

Analysis.Calcd. for C H O (388.49): C, 71.10; H, 8.30. Found: C, 70.91;H, 8.02.

Example 13 .3,20-bisetl1ylenedioxy-S-pregnene- 1Ia,12/3-di0l Thirtygrams of sodium metal are added in small portions to a refluxingsolution of 3,20-bisethylenedioxy-5- pregnene-lZfi-ol-ll-one in 500 ml.of n-butyl alcohol over a three hour period. The resulting solution isthen refluxed for three hours during which time the sodium dissolvedcompletely. The orange solution is then slowly diluted with 50 ml. ofwater whereupon crystals slowly separate. An additional 100 ml. of waterare then added slowly and the mixture filtered and dried to give about1.07 grams of 3,20-bisethylenedioxy-S-dehydropregnene- 11oc,l2[3-di0lhaving a melting point about 185-187", [ad -26.2 (chloroform).

Arzalysis.-Calcd. for C H O (434.55): C, 69.09, H, 8.81. Found: C,68.85; H. 8.63.

Example 14.-] 1 11,1 2 fi-d ihydroxy progesterone A solution of 100 mgof 3,20-bisethylenedioxy-S-pregnene-l1a,12;8-diol in 40 ml. of reagentgrade methanol and 1.4 ml. of a solution of 8 ml. of sulfuric acid per92 ml. of water is refluxed for 40 minutes. The solution is then cooled,neutralized carefully with 5% sodium bicarbonate, diluted with ml. ofwater and extracted with chloroform. The chloroform extract is washedwith water until neutral and evaporated to dryness, in vacuo.Crystallization of the residue from acetone-hexane gives about 54.3 mg.of 1la,1ZB-dihydroxyprogesterone having a melting point of about 152154[a] +108 (chloroform),

ME... 241 a (6, 14,600

Analysis.Calcd. for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.71;H, 8.88.

Example 15.11a,1Zfl-dihydroxyprogesterone 11,12-acet0nide A solution of700 mg. of 3,20-bisethylenedioxy-S-pregnene-11a,125-diol in ml. ofreagent grade acetone containing 0.1 ml. of perchloric acid is kept atroom temperature for eighteen hours. It is then neutralized I with 5%sodium bicarbonate and diluted carefully with water whereupon crystalsseparate. The crystals are fil- 9 tered, washed with water, dried togive 11a,l2B-dihydroxyprogesterone 11,12-acetonide having a meltingpoint of about 199-201", [M +222 (chloroform),

Example 16.11 a,] ZB-dfhydroxy progesterone 11,12-acet0nide Followingthe procedure of Example 15 but substituting1la,12fl-dihydroxyprogesterone for the3,20-bisethylenedioxy-S-pregnene-I1a,12fi-diol there is obtained11a,12/3- dihydroxyprogesterone 11,12-acetonide.

Example 1 7 .-1 1 0a,] ZB-dihydroxyprogesterone 1 1,12-acet0phenonideFollowing the procedure of Example 15 or 16 but substitutingacetophenone for the acetone there is obtained11a,12/3-dihydroxyprogesterone 11,12-acetophenonide.

Example 18.] 1 0a,] Za-dihydroxyprogesterone A solution of 500 mg. of3,20-bisethylenedioxy-5-pregnene-11a,12a-diol in 200 ml. of reagentgrade methanol and 7 ml. of a solution of 8 ml. of sulfuric acid in 92ml. of water is refluxed for forty minutes. It is then cooled,neutralized carefully with 5% sodium bicarbonate, diluted with water andextracted with chloroform. The chloroform extract is then washed withwater and evaporated to dryness, in vacuo. The residue on platechromatography using alumina (V) as adsorbant and chloroformethylacetate (4:1;vzv) as developing solvent gives a band at Rf 0.5detectable by UV. which on separation and elutionwith ethyl acetategives a residue which on crystallization from acetone-hexane yieldsabout 150 mg. of 11a,12a-dihydroxyprogesterone having a melting point of158160, [11], +142 (chloroform),

Analysis.-Calcd. for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.86;H, 8.76.

Example 19.11 ,8,1ZB-dihydroxyprogesterone Following the procedure ofExample 18 but substituting3,20-bisethylenedioxy-5-pregnene-11,8,12,8-diol for the 3,20-bisethylenedioxy-5-pregnene-11a,12a-diol there is obtained 116,128dihydroxyprogesterone having melting point about 188-189", +116(chloroform),

Analysis-Called. for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.74;H, 8.82.

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of steroids of theformulae and the 1,2-dehydro derivatives thereof, wherein R is selectedfrom the group consisting of hydroxy and a-acyloxy, P is selected fromthe group consisting of hydrogen, lower alkyl, halo lower alkyl, carboxylower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryllower a kyl, monocyclic heterocyclic and monocyclic heterocylic loweralkyl, Q is selected from the group consisting of lower alkyl, halolower alkyl, carboxy lower alkyl, monocyclic, cycloalkyl, monocyclicaryl, monocyclic aryl lower alkyl, monocyclic heterocyclic andmonocyclic heterocyclic lower alkyl, and together with the carbon atomto which they are joined, P and Q are selected from the group consistingof cycloalkyl and monocyclic heterocyclic.

2. llfi,12B-lower alkylidenedioxyprogesterone.

3. 1lfi,125-dihydroxyprogesterone 11,12-acetonide.

4. 115,128 dihydroxyprogesterone 11,12 aceto henonide.

5. 11B,1ZB-dihydroxy-l-dehydroprogesterone 11,12-acetophenonide.

6. 11a,12a-lower alkylidenedioxyprogesterone.

7. 11a,12u-dihydroxyprogesterone 11,12-acetonide.

8. 11oz,120c dihydroxyprogesterone, 11,12 acetophenonide.

9. 11a,12u-dihydroxy-l-dehydroprogesterone 11,12-acetophenonide.

10. The 3,20-bis-lower alkylene ketal of 11a,12a-dihydroxyprogesterone.

11. The 3,20-bis-ethylene ketal of 11a,12a-dihydroxyprogesterone.

12. The 3,20-bis-lower alkylene ketal of 115,12/8-dihydroxyprogesterone.

13. The 3,20-bis-ethylene ketal of 11,6,12B-dihydroxyprogesterone.

. 1 1 B, l2a-dihydroxyprogesterone. 1 1a,12t?-dihydroxyprogesterone.11oc,12B-1OWCI' alkylidenedioxyprogesterone.

1 1oz, 12a-dihydroxyprogesterone. 1 1,6,1Zfi-dihydroxyprogesterone.

References Cited by the Examiner UNITED STATES PATENTS 2,751,400 6/1956Nathan 260397.45 3,056,731 10/1962 Isono et a1. 260397.45 3,185,7135/1965 Becker et al 260397.3

LEWIS GOTTS, Primary Examiner.

JOHNNIE R. BROWN, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THEFORMULAE